[go: up one dir, main page]

US4965365A - Imidazole derivatives and a process for the preparation thereof - Google Patents

Imidazole derivatives and a process for the preparation thereof Download PDF

Info

Publication number
US4965365A
US4965365A US07/356,013 US35601389A US4965365A US 4965365 A US4965365 A US 4965365A US 35601389 A US35601389 A US 35601389A US 4965365 A US4965365 A US 4965365A
Authority
US
United States
Prior art keywords
anion
compound
chloride
derivatives
zinc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US07/356,013
Inventor
Amparo S. Sanfeliu
Lucia S. Tuero
Maria J. Delgado de Molina Gonzalez
Antonio B. Vinas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratorios Vinas SA
Original Assignee
Laboratorios Vinas SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratorios Vinas SA filed Critical Laboratorios Vinas SA
Assigned to LABORATORIOS VINAS, S.A. reassignment LABORATORIOS VINAS, S.A. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: DELGADO DE MOLINA GONZALE, MARIA J., SANFELIU, AMPARO S., TUERO, LUCIA S., VINAS, ANTONIO B.
Application granted granted Critical
Publication of US4965365A publication Critical patent/US4965365A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the invention relates to a process for the preparation of imidazole derivatives having the general formula I: ##STR2## where X is an anion of pharmaceutically acceptable acids, a is 1, 2, 3, 4 or 5; b is 1, 2, 3, 4, 5, 6 or 7; c is 1, 2, 3 or 4; d is twice a minus c; and n is 0, 1, 2 or 3.
  • the invention also relates to the derivatives of formula I, which have antiulcer properties.
  • the imidazole derivatives of the invention provide advantages on improving the antiulcer properties of cimetidine.
  • X may be an anion of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid and others; or an anion of non-toxic organic acids such as mono- and dicarboxylic aliphatic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aromatic and aliphatic sulphonic acids and others.
  • inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid and others
  • non-toxic organic acids such as mono- and dicarboxylic aliphatic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aromatic and aliphatic sulphonic acids and others.
  • X may be chloride, bromide, iodide, fluoride, sulphate, phosphate, chlorate, nitrate, sulphamate, maleate, fumarate, succinate, oxalate, acetate, acexamate, tartrate, citrate, camphorsulphonate, mandelate, butine-1,4-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, benzenesulphonate, toluenesulphonate, phenylacetate, salicylate, beta-hydroxybutyrate, glycolate, methanesulphonate and the like.
  • the process of the invention is characterised in that cimetidine is reacted with an X anion containing zinc compound.
  • said zinc compound is an organic or inorganic zinc salt and the reaction is carried out in a polar organic solvent such as dimethylformamide, dimethylsulphoxide, acetone, low molecular weight alcohols, etc, or in an organicoaqueous mixture.
  • a polar organic solvent such as dimethylformamide, dimethylsulphoxide, acetone, low molecular weight alcohols, etc, or in an organicoaqueous mixture.
  • An alcohol will preferably be used.
  • the reaction temperature may reach the boiling point of the solvent, preferably from room temperature to 60° C.
  • an alkali or alkaline earth hydroxide may be added or not at the end to alkaline pH, preferably to pH 8. Water may also be added or not, when the reaction has been carried out in an organic solvent alone.
  • the compounds are prepared in solid form or in the form of a thick oil which, after removal of the solvent under vacuum, becomes a solid.
  • the formula I compounds have exhibited a potent antiulcer activity.
  • the inhibition of histamine induced gastric secretion "in vivo" in the rat after administration of these Zn-cimetidine compounds i.p. at dose levels of 5 to 50 mg/kg reaches pH recovery levels of 75%.
  • the antiulcer activity in the rat against ethanol induced ulcers has proved to be satisfactory at dose levels of 100 to 400 mg/kg, p.o., a total ulcer inhibition having been observed in certain cases.
  • This activity was measured in Wistar rats of 240 ⁇ 20 g body weight. An endovenous perfusion of a histamine solution stimulated the gastric acid secretion, causing a drop in the intragastric pH. Thereafter, this compound was administered i.p. and the increase in gastric pH caused was evaluated.
  • the synthetised product has an antiulcer activity far superior to that of cimetidine.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Imidazole derivatives and a process for the preparation thereof.
The imidazole derivatives have remarkable antiulcer properties and are of the following formula: ##STR1## where X is an anion of pharmaceutically acceptable acids; a is 1, 2, 3, 4 or 5; b is 1, 2, 3, 4, 5, 6 or 7; c is 1, 2, 3 or 4; d is twice a minus c; and n is 0, 1, 2 or 3.
The process for the preparation thereof is based on reacting cimetidine and a zinc compound containing the anion X.

Description

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a process for the preparation of imidazole derivatives having the general formula I: ##STR2## where X is an anion of pharmaceutically acceptable acids, a is 1, 2, 3, 4 or 5; b is 1, 2, 3, 4, 5, 6 or 7; c is 1, 2, 3 or 4; d is twice a minus c; and n is 0, 1, 2 or 3.
The invention also relates to the derivatives of formula I, which have antiulcer properties.
2. Reference to the Prior Art
Chronic gastric and doudenal ulcers are frequent diseases for which there exists a variety of treatments, including dietetic measures, treatment with drugs and surgery. Among these, special attention has been paid in recent years to treatment with secretion inhibitors, one of the most widely used secretion inhibitors around the world being cimetidine of formula II. ##STR3##
SUMMARY OF THE INVENTION
The imidazole derivatives of the invention provide advantages on improving the antiulcer properties of cimetidine.
In the imidazole derivatives of formula I, X may be an anion of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid and others; or an anion of non-toxic organic acids such as mono- and dicarboxylic aliphatic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aromatic and aliphatic sulphonic acids and others.
Therefore, X may be chloride, bromide, iodide, fluoride, sulphate, phosphate, chlorate, nitrate, sulphamate, maleate, fumarate, succinate, oxalate, acetate, acexamate, tartrate, citrate, camphorsulphonate, mandelate, butine-1,4-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, benzenesulphonate, toluenesulphonate, phenylacetate, salicylate, beta-hydroxybutyrate, glycolate, methanesulphonate and the like.
The process of the invention is characterised in that cimetidine is reacted with an X anion containing zinc compound.
Preferably said zinc compound is an organic or inorganic zinc salt and the reaction is carried out in a polar organic solvent such as dimethylformamide, dimethylsulphoxide, acetone, low molecular weight alcohols, etc, or in an organicoaqueous mixture. An alcohol will preferably be used. The reaction temperature may reach the boiling point of the solvent, preferably from room temperature to 60° C. Depending on the type of compound it is wanted to isolate, an alkali or alkaline earth hydroxide may be added or not at the end to alkaline pH, preferably to pH 8. Water may also be added or not, when the reaction has been carried out in an organic solvent alone.
The compounds are prepared in solid form or in the form of a thick oil which, after removal of the solvent under vacuum, becomes a solid.
The formula I compounds have exhibited a potent antiulcer activity. Thus the inhibition of histamine induced gastric secretion "in vivo" in the rat after administration of these Zn-cimetidine compounds i.p. at dose levels of 5 to 50 mg/kg, reaches pH recovery levels of 75%. The antiulcer activity in the rat against ethanol induced ulcers has proved to be satisfactory at dose levels of 100 to 400 mg/kg, p.o., a total ulcer inhibition having been observed in certain cases.
To facilitate the explanation, the invention is illustrated, but not limited, by the following examples:
EXAMPLE 1 Preparation of Zn4 (cimetidine)6 Cl3 (OH)5
A solution of 0.72 g of zinc chloride in 18 ml of water was added dropwise with stirring over a solution of 4.0 g of cimetidine in 130 ml of ethanol. The mixture was stirred for 10 min and 1N sodium hydroxide was added slowly to pH 8. The white precipitate formed was filtered off, washed with ethanol and dried under vacuum at 60° C.
Elementary analysis for C60 H101 Cl3 N36 O5 S6 Zn4 Calculated: C 36.64; H 5.18; Cl 5.41; N 25.64; O 4.07; S 9.78 and Zn 13.30. Found: C 37.11; H 4.87; Cl 5.43; N 26.00; S 10.12 and Zn 13.68.
IR(KBr): 3160, 2970, 2210, 2170, 1590, 1490 and 1110 cm-1.
HPLC purity (μ-bondpack C-18; buffer H3 PO4 (pH 2.3)/acetonitrile: 90/10; 1.1 ml/min.; lambda=228 nm): 98.5%.
UV (H2 SO4 0.1N): lambda max 219±2 nm A (1%, 1 cm): 631.
MS(FAB), m/z: 253, 275, 505, 527, 603, 605, 607 and 757.
EXAMPLE 2 Preparation of Zn3 (cimetidine)4 (CH3 COO)2 (OH)4
1.16 g of zinc acetate dihydrate, dissolved in 15 ml of water, were added with stirring over a solution of 4.0 g of cimetidine in 80 ml of methanol at 60° C. After 5 minutes stirring, 1N sodium hydroxide was added to pH 8.1. The precipitate obtained was filtered, washed with methanol and dried under vacuum in a muffle at 60° C.
Elementary analysis for C44 H74 N24 O8 S4 Zn3 : Calculated: C 37.98; H 5.36; N 24.16; O 9.20; S 9.22 and Zn 14.09. Found: C 38.45; H 5.37; N 24.55; S 9.50 and Zn 14.15.
IR(KBr): 3412, 2922, 2211, 2169, 1586, 1484 and 1103 cm-1.
HPLC purity (under the same conditions as in Example 1): 101.2%.
UV (H2 SO4 0.1N): lambda max 218±2 nm A (1%, 1 cm): 587.
MS(FAB), m/z: 253, 275 and 375.
EXAMPLE 3 Preparation of Zn(cimetidine)Cl2
5.0 g of cimetidine dissolved in 70 ml of ethanol were added slowly over a solution of 2.7 g of zinc chloride in 30 ml of ethanol. The oil formed and the ethanol were separated by decantation. A further 40 ml of ethanol were added, stirring was continued for 15 minutes and the products were separated again by decantation. The oil thus obtained was dried under vacuum at 70° C., was ground and dried again.
Elementary analysis for C10 H16 Cl2 N6 SZn: Calculated: C 30.91; H 4.15; Cl 18.25; N 21.62; S 8.25 and Zn 16.82. Found: C 31.17; H 3.95; Cl 17.88; N 21.80; S 8.20 and Zn 16.62.
IR(KBr): 3628, 3411, 2923, 2208, 1616, 1507, 1437, 1227 and 1087 cm-1.
1 H NMR (CD3 SOCD3, TMS as internal standard). delta: 2.20 (s, 3H); 2.68 (d, 3H); 3.1-3.5 (multiplet, 5H); 3.81 (s, 2H); 6.9-7.1 (multiplet, 2H) and 7.91 (s, 1H).
HPLC purity (under the same conditions as in Example 1): 98.7%.
UV (H2 SO4 0.1N): lambda max 218±2 nm A (1%, 1 cm): 517.
MS(FAB), m/z: 253 and 275.
Experiments are described below to show the therapeutical activity of the compound obtained according to Example 3.
Antiulcer Activity
The antiulcer activity of Zn(cemetidine)Cl2 has been studied in different experimental models, some of which are described below:
(A) histamine induced gastric acid secretion model "in vivo" in the rat.
This activity was measured in Wistar rats of 240±20 g body weight. An endovenous perfusion of a histamine solution stimulated the gastric acid secretion, causing a drop in the intragastric pH. Thereafter, this compound was administered i.p. and the increase in gastric pH caused was evaluated.
At the same time when a group of control animals was administered physiological serum, instead of a compound of the present invention, no significant pH recovery was observed. The results are illustrated in the following table:
______________________________________                                    
                          pH Recovery                                     
Compound                  (%)                                             
______________________________________                                    
Zn.sub.4 (cimetidine).sub.6 Cl.sub.3 (OH).sub.5                           
                   (15 mg/kg) 56.5                                        
Zn.sub.3 (cimetidine).sub.4 (CH.sub.3 COO).sub.2 (OH).sub.4               
                   (100 mg/kg)                                            
                              55.6                                        
Zn(cimetidine)Cl.sub.2                                                    
                   (15 mg/kg) 65.5                                        
Control                       ±2.4                                     
______________________________________                                    
 Thus, at a dose level of 15 mg/kg, a 65.5% pH recovery was obtained.
(B) Necrotic agent model.
The activity of this compound vs cimetidine at equimolecular doses and a control group administered a vehicle was tested using the necrotic agent model, in this case ethanol, described by A. Robert et al. (Gastroenterology, 77: 433, 1979).
The following table summarises the lesion indices (in mm of ulcer) of the three groups studied, as well as the % inhibition of ulcers in the treated groups vs the control (means values±standard error of the mean).
______________________________________                                    
            mm damaged                                                    
                     % inhibition                                         
______________________________________                                    
Control       91.4 ± 8.1                                               
                         --                                               
Cimetidine    .sup. 63.7 ± 7.7.sup.a                                   
                         30.3                                             
______________________________________                                    
 t test: a, p< 0.05 vs control; b, p< 0.001 vs control and c, p< 0.001 vs 
 cimetidine.
As may be seen, the synthetised product has an antiulcer activity far superior to that of cimetidine.

Claims (11)

What we claim is:
1. An imidazole derivative corresponding to a compound of formula I, ##STR4## where X is an anion selected from the group consisting of chloride and acetate; a is 1, 2, 3, 4 or 5;
b is 1, 2, 3, 4, 5, 6 or 7; c is 1, 2, 3 or 4;
d is equal to (2a-c) and n is 0, 1, 2 or 3.
2. The derivatives of claim 1, characterised in that X is the chloride anion, a=4, b=6, c=3, d=5 and n=0.
3. The derivatives of claim 1, characterised in that X is the acetate anion, a=3, b=4, c=2, d=4 and n=0.
4. The derivatives of claim 1, characterised in that X is the chloride anion, a=b=1, c=2, d=n=0.
5. A process for the preparation of imidazole derivatives having the general formula I: ##STR5## where X is an anion of pharmaceutically acceptable acids, a is 1, 2, 3, 4 or 5; b is 1, 2, 3, 4, 5, 6 or 7; c is 1, 2, 3 or 4; d is twice a minus c; and n is 0, 1, 2 or 3, characterised in that cimetidine is reacted with a zinc compound containing the X anion.
6. The process of claim 5, characterised in that said compound is a zinc salt containing the X anion.
7. The process of claim 5, characterised in that the X anion is selected from the group formed by chloride, bromide, iodide, fluoride, sulphate, phosphate, chlorate, nitrate, sulphamate, maleate, fumarate, succinate, oxalate, acetate, acexamate, tartrate, citrate, camphorsulphonate, mandelate, butine-1,4-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, benzenesulphonate, toluenesulphonate, phenylacetate, salicylate, beta-hydroxybutyrate, glycolate and methanesulphonate.
8. The process of claim 5, characterised in that said compound is zinc chloride.
9. The process of claim 5, characterised in that said compound is zinc acetate dihydrate.
10. The process of claim 5, characterised in that the reaction is carried out in a polar solvent.
11. The process of claim 10, characterised in that said solvent is a low molecular weight alcohol, dimethylformamide, dimethylsulphoxide, acetone or aqueous mixtures of the said solvents.
US07/356,013 1988-05-26 1989-05-23 Imidazole derivatives and a process for the preparation thereof Expired - Fee Related US4965365A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES8801655 1988-05-26
ES8801655A ES2009921A6 (en) 1988-05-26 1988-05-26 Imidazole derivatives and a process for the preparation thereof

Publications (1)

Publication Number Publication Date
US4965365A true US4965365A (en) 1990-10-23

Family

ID=8256534

Family Applications (1)

Application Number Title Priority Date Filing Date
US07/356,013 Expired - Fee Related US4965365A (en) 1988-05-26 1989-05-23 Imidazole derivatives and a process for the preparation thereof

Country Status (7)

Country Link
US (1) US4965365A (en)
JP (1) JPH0225468A (en)
DE (1) DE3916803A1 (en)
ES (1) ES2009921A6 (en)
FR (1) FR2631963A1 (en)
GB (1) GB2218987B (en)
IT (1) IT1230084B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5221688A (en) * 1990-04-25 1993-06-22 Glaxo Group Limited Imidazole derivatives
EP0376113B1 (en) * 1988-12-26 1993-08-04 Laboratorios Vinas S.A. A process for the preparation of an acexamic acid derivative
WO1994020148A1 (en) * 1993-03-12 1994-09-15 Mallinckrodt Medical, Inc. Imidazole based nitrogen-sulfur ligands useful in radiographic imaging agents
US20030158118A1 (en) * 2001-11-26 2003-08-21 Weidner Morten Sloth Combination of cimetidine and cysteine derivatives for treating cancer
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9004328D0 (en) * 1990-02-27 1990-04-25 Glaxo Group Ltd Chemical compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4381395A (en) * 1981-04-03 1983-04-26 Sk & F Lab Co. Process for preparing an imidazole derivative
US4413129A (en) * 1978-12-27 1983-11-01 Sogo Pharmaceutical Company, Ltd. Process for preparing the H2 -receptor antagonist cimetidine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5933270A (en) * 1982-08-19 1984-02-23 Hamari Yakuhin Kogyo Kk Zinc salt of carnosine and preparation thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4413129A (en) * 1978-12-27 1983-11-01 Sogo Pharmaceutical Company, Ltd. Process for preparing the H2 -receptor antagonist cimetidine
US4381395A (en) * 1981-04-03 1983-04-26 Sk & F Lab Co. Process for preparing an imidazole derivative

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0376113B1 (en) * 1988-12-26 1993-08-04 Laboratorios Vinas S.A. A process for the preparation of an acexamic acid derivative
US5221688A (en) * 1990-04-25 1993-06-22 Glaxo Group Limited Imidazole derivatives
WO1994020148A1 (en) * 1993-03-12 1994-09-15 Mallinckrodt Medical, Inc. Imidazole based nitrogen-sulfur ligands useful in radiographic imaging agents
US5623077A (en) * 1993-03-12 1997-04-22 Mallinckrodt Medical, Inc. Imidazole based nitrogen sulfur ligands useful in radiographic imaging agents
US20030158118A1 (en) * 2001-11-26 2003-08-21 Weidner Morten Sloth Combination of cimetidine and cysteine derivatives for treating cancer
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

Also Published As

Publication number Publication date
GB2218987B (en) 1991-10-09
ES2009921A6 (en) 1989-10-16
DE3916803A1 (en) 1989-12-14
IT8920611A0 (en) 1989-05-23
IT1230084B (en) 1991-10-05
JPH0225468A (en) 1990-01-26
GB2218987A (en) 1989-11-29
FR2631963A1 (en) 1989-12-01
GB8911838D0 (en) 1989-07-12

Similar Documents

Publication Publication Date Title
CA1226223A (en) Pharmaceutical compositions containing benzimidazole compounds
US4636499A (en) Sulphenamides
EP0079872B1 (en) Antifibrinolytically active compounds
US5462959A (en) 4-aryl-imidazole derivatives
NO155490B (en) ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 4-) 1 &#34;-HYDROXY-2&#34; - (N-IMIDAZOLYL) ETHYL) BIBENZYL.
US4965365A (en) Imidazole derivatives and a process for the preparation thereof
US5049566A (en) Imidazole [4,5-c] pyridine derivatives having gastric acid antisecretory activity and pharmaceutical compositions containing them
US4035370A (en) Alkaloid esters
EP0405602A1 (en) New Zinc derivatives of anti-inflammatory drugs having improved therapeutic activity
US4921887A (en) Thiazole compounds and pharmaceutical composition comprising the same
SU923368A3 (en) Process for producing benzimidazole derivatives or their salts
US5025015A (en) Thioformamidines, and use as medicaments
JPH0251914B2 (en)
US4956466A (en) Thiazole derivatives and process for the preparation thereof
EP0350422B1 (en) Propargylguanidine derivatives and process for the preparation thereof
US4277496A (en) Methods of treating mammals suffering from inflammation and pain
US5068238A (en) 2-alkyliminobenzothiazoline derivatives, processes for preparing them and medicinal products containing them
US5041557A (en) Furan derivatives
DE2118635A1 (en) Acylaminocephalosporanic acids and processes for their preparation
AU726083B2 (en) New forms of organic salts of N&#39;N-diacetylcystine
US4223146A (en) 4,5,6,7-Tetrahydroimidazo-[4,5-c]-pyridine derivatives
US4273777A (en) Methods of treating mammals suffering from inflammation and pain
US4256760A (en) Methods of treating mammals suffering from inflammation and pain
US4517185A (en) 2-Pyrrolin-3-carbonitrile derivatives, and pharmaceutical compositions containing them and their anti-inflammatory and ulcer protective activity
PL96042B1 (en) METHOD OF MAKING NEW AMINO DERIVATIVES OF ASIDOPHENOLS

Legal Events

Date Code Title Description
AS Assignment

Owner name: LABORATORIOS VINAS, S.A., SPAIN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:SANFELIU, AMPARO S.;TUERO, LUCIA S.;DELGADO DE MOLINA GONZALE, MARIA J.;AND OTHERS;REEL/FRAME:005214/0523

Effective date: 19890421

CC Certificate of correction
REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Lapsed due to failure to pay maintenance fee

Effective date: 19941026

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362